Persistent negative and cognitive symptoms are a primary cause of chronic disability and poor long-term[unreadable] outcome in schizophrenia. Deficits involve sensory-level disturbances, as well as abnormalities of higher[unreadable] level cognition. Phencyclidine (PCP) and other antagonists of N-methyl-D-aspartate (NMDA)-mediated[unreadable] neurotransmission induce symptoms and cognitive deficits that closely resemble those of schizophrenia and[unreadable] incorporate sensory, as well as higher cognitive changes, indicating a potentially critical role of NMDA[unreadable] receptors in the etiopathology of negative symptoms and cognitive dysfunction. NMDA receptors are[unreadable] modulated in vivo by glycine and D-serine, which bind to the glycine modulatory site (GMS) of the NMDA[unreadable] receptor complex. Clinical trials with GMS agonists have yielded highly encouraging clinical data with regard[unreadable] to negative symptoms, although effects on neurocognition remain to be determined. The present project will[unreadable] investigate effects of D-serine on neurocognitive deficits associated with schizophrenia, using both eventrelated[unreadable] potential (ERP) and behavioral measures sensitive to bottom-up effects of early cortical dysfunction.[unreadable] The project consists of two components. First, neurocognitive measures will be added to a recently funded[unreadable] study of D-serine treatment in both chronic and prodromal subjects in order to evaluate the degree to which[unreadable] GMS agonist treatment can reverse or prevent neurocognitive deficits associated with schizophrenia.[unreadable] Second, parallel studies in transgenic mouse models will evaluate the degree to which ERP deficits in[unreadable] schizophrenia can be reproduced by genetic manipulations aimed at the NMDA GMS.